The present invention relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.cf, during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in mammals, including humans, using an NK-1 antagonist. It also relates to a method of treating or preventing such disorders in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, pyrrolidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds that are substance P receptor antagonists.
The following references refer, collectively, to quinuclidine, piperidine, ethylene diamine, pyrrolidine and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992; U.S. Pat. No. 5,232,929, which issued on Aug. 3, 1993; World Patent Application WO 92/20676, published Nov. 26, 1992; World Patent Application WO 93/00331, published Jan. 7, 1993; World Patent Application WO 92/21677, published Dec. 10, 1992; World Patent Application WO 93/00330, published Jan. 7, 1993; World Patent Application WO 93/06099, published Apr. 1, 1993; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 92/06079, published Apr. 16, 1992; World Patent Application WO 92/12151, published Jul. 23, 1992; World Patent Application WO 92/15585, published Sep. 17, 1992; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 93/19064, published Sep. 30, 1993; World Patent Application WO 94/08997, published Apr. 28, 1994; World Patent Application WO 94/04496, published Mar. 3, 1994; U.S. patent application Ser. No. 988,653, filed Dec. 10, 1992; U.S. patent application Ser. No. 026,382, filed Mar. 4, 1993; U.S. patent application Ser. No. 123,306, filed Sep. 17, 1993, and U.S. patent application Ser. No. 072,629, filed Jun. 4, 1993. All of the foregoing World Patent Applications designate the United States and were filed in the U.S. Receiving Office of the PCT. The foregoing patents and patent applications are incorporated herein by reference in their entirety.
This invention relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to such mammal an amount of a substance P receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to such mammal an amount of a NK-1 receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of ring system A;
AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR2R3 is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the xe2x80x94CH2PR3 sidechain is attached to a carbon atom of ring AAA;
P is NR2, O, S, SO or SO2;
Q is SO2, NH, 
wherein the point of attachment of said 
to ring AAA is the nitrogen atom and the point of attachment to X5 is the sulfur atom;
W1 is hydrogen, halo or (C1-C6)alkyl, Sxe2x80x94(C1-C3)alkyl, halo or (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
W2 is hydrogen, (C1-C6)alkyl, Sxe2x80x94(C1-C3)alkyl, halo or (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, xe2x80x94S(O)vxe2x80x94(C1-C6)alkyl wherein v is zero, one or two, halo or (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
X1 is hydrogen, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms or (C1-C10)alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms, trif luoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)-alkylamino, di-(C1-C6)alkylamino, 
xe2x80x83(C1-C6)xe2x80x94
xe2x80x83hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, 
X5 is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to three fluorine atoms and (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms;
R1 is selected from amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, xe2x80x94S(O)vxe2x80x94(C1-C10)-alkyl wherein v is zero, one or two, xe2x80x94S(O)v-aryl wherein v is zero, one or two, xe2x80x94O-aryl, xe2x80x94SO2NR4R5 wherein each of R4 and R5 is, independently, C1-C6)alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, 
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, xe2x80x94N(SO2xe2x80x94(C1-C10)alkyl)2 and 
and wherein the aryl moieties of said xe2x80x94S(O)v-aryl, xe2x80x94O-aryl and 
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and halo;
or R1 is a group having the formula 
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the R2R3NCH2 side chain;
the dotted lines in formula Ib represent that one of the Xxe2x80x94Y and Yxe2x80x94Z bonds may optionally be a double bond;
X is selected from xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94CH[(C1-C6)alkyl]xe2x80x94, xe2x95x90C[(C1-C6)alkyl]xe2x80x94, xe2x80x94CH(C6H5)xe2x80x94 and xe2x95x90C(C6H5)xe2x80x94;
Y is selected from Cxe2x95x90O, Cxe2x95x90NR4, Cxe2x95x90S, xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x95x90C[(C1-C6)alkyl]xe2x80x94, xe2x80x94CH[(C1-C6)alkyl]xe2x80x94, xe2x95x90C(C6H5)xe2x80x94, xe2x80x94CH(C6H5)xe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x95x90C(halo)xe2x80x94, xe2x95x90C(OR4)xe2x80x94, xe2x95x90C(SR4)xe2x80x94, xe2x95x90C(NR4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and SO2, wherein the phenyl moieties of said xe2x95x90C(C6H5)xe2x80x94 and xe2x80x94CH(C6H5)xe2x80x94 may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said xe2x95x90[(C1-C6)alkyl]xe2x80x94 and xe2x80x94CH[C1-C6)alkyl]xe2x80x94 may optionally be substituted with from one to three fluorine atoms;
Z is selected from xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x95x90C(C6H5)xe2x80x94, xe2x80x94CH(C6H5)xe2x80x94, xe2x95x90C[(C1-C6)alkyl]xe2x80x94 and xe2x80x94CH[(C1-C6)alkyl]xe2x80x94;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
R4 is (C1-C6)alkyl or phenyl;
R2 is hydrogen or xe2x80x94CO2(C1-C10)alkyl;
R3 is selected from 
wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carbonyl;
R7 is selected from (C3-C4) branched alkyl, (C5-C6) branched alkenyl, (C5-C7)cycloalkyl, and the radicals named in the definition of R6;
R8 is hydrogen or (C1-C6)alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms;
Y1 is (CH2)1 wherein 1 is an integer from one to three, or Y1 is a group of the formula 
Z1 is oxygen, sulfur, amino, (C1-C3)alkylamino or (CH2)n, wherein n is zero, one or two;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from one to six, wherein the ring containing (CH2)z may contain from zero to three double bonds, and one of the carbons of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
o is two or three;
p is zero or one;
r is one, two or three;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms and (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms;
X4 is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R17;
R12 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6)alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)-alkylamino, 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1-C6)alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (xe2x95x90O), cyano, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)alkylamino, 
xe2x80x83and the radicals set forth in the definition of R12; 
xe2x80x83NHCH2R18, SO2R18, GR20 CO2H or one of the radicals set forth in any of the definitions of R12, R14 and R15;
R17 is oximino (xe2x95x90NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R15; and
R18 is (C1-C6)alkyl, hydrogen, phenyl or phenyl (C1-C6)alkyl;
G is selected from the group consisting of CH2, nitrogen, oxygen, sulfur and carbonyl;
R20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae 
xe2x80x83wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH2)n or (CH2)n+1 may be optionally substituted with (C1-C6)alkyl or (C2-C6)spiroalkyl, and either any two of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
with the proviso that (a) when m is 0, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1-C6)alkyl, hydroxy-(C1-C6)alkyl and (C1-C6)alkoxy-(C1-C6)alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 cannot both be hydrogen; (e) when R14 or R15 is attached to a carbon atom of X or (CH2)y that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (f) neither R14, R15, R16 nor R17 can form a ring with R13;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
The fused bicyclic nucleus of compounds of the formula Ib to which W and the xe2x80x94CN2NR2R3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (1) through (47A) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(1) A compound of the formula Ia or Ib wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring of R3 are in a cis configuration. (When R3 is a group of the formula VII or VIII, xe2x80x9ca cis configurationxe2x80x9d, as used herein, means that the non-hydrogen substituent at position xe2x80x9c3xe2x80x9d is cis to R12).
(2) A compound of the formula Ia wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; A is phenyl or indolinyl; W is (C1-C3)alkoxy optionally substituted with from one to five fluorine atoms; and R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and R may optionally be substituted with one or two (C1-C3)alkyl moieties.
(3) A compound of the formula Ib wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl or benzimidazolyl; and W is (C1-C6)alkoxy optionally substituted with from one to five fluorine atoms.
(4) A compound as defined in paragraph 1, 2 or 3 above wherein: (a) R3 is a group of the formula III and R9 is benzhydryl; (b) R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero and X4 is xe2x80x94(CH2)3xe2x80x94; or (c) R3 is a group of the formula IX, r is two and R19 is benzhydryl.
(5) A compound of the formula Ia wherein: (a) R3 is a group of the formula III wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, R9 is benzhydryl and A is phenyl; or (b) R3 is a group of the formula VII wherein R12 and the substituent at position xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, A is phenyl, R2 is phenyl, each of R2, R13, R14, R15 and R16 is hydrogen, m is zero, W is methoxy or isopropoxy, X4 is xe2x80x94(CH2)3xe2x80x94 and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.
(6) A compound of the formula Ib wherein R3 is a group of the formula IX wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, R19 is benzhydryl, r is two and the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzisoxazolyl or benzthiazolyl.
(7) A compound of the formula Ib wherein R3 is a group of the formula IX, R19 is benzhydryl, the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzisoxazolyl, and W is methoxy.
(8) A compound of the formula Ib wherein R3 is a group of the formula VII, R12 is phenyl, each of R13, R , R15 and R16 is hydrogen, m is zero, X4 is xe2x80x94(CH2)3xe2x80x94, and the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzothiazolyl, benzoxazolyl or benzimidazolyl.
(9) A compound of the formula Ia wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, m is zero, X is xe2x80x94(CH2)3xe2x80x94, A is phenyl, W is methoxy, and R is selected from thiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.
(10) A compound of the formula Ia or Ib that is selected from:
(2S, 3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2-phenylpiperidine;
(2S, 3S)-3-[5-(2-imidazolyl)-2-methoxybenzyl]amino-2-phenylpiperidine;
(2S, 3S)-3-[2-methoxy-5-(2-oxopyrrolidinyl)benzyl]amino-2 -phenylpiperidine;
(2S, 3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)benzyl]-amino-2-phenylpiperidine;
(2S, 3S)-3-[2-methoxy-5-(1,2,3-thiadiazol-4-yl)benzyl]-amino-2-phenylpiperidine;
(2S, 3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-3-[2-methoxy-5-(5-oxazolyl)benzyl]amino-2-phenylpiperidine;
(2S, 3S)-(6-methoxy-2-methyl-benzoxazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; and
(1SR, 2SR, 3SR, 4RS)-3-[6-methoxy-3-methylbenzisoxazol-5-yl]methylamino-2-benzhydrylazanorbornane.
(11) A compound of the formula Ic, wherein R3 is a group of the formula II, III, VII or IX; R2 is hydrogen; ring AA is phenyl or indolinyl; W1 is (C1-C3)alkoxy optionally substituted with from one to three fluorine atoms; and R1 is S(O)vxe2x80x94(C1-C10)alkyl wherein v is zero, one or two, S(O)v-aryl wherein v is zero, one or two, xe2x80x94O-aryl, 
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, xe2x80x94N(SO2xe2x80x94(C1-C10)alkyl)2 or 
wherein said aryl is phenyl or benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and halo.
(12) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula II, o is two, and each R6 and R7 is phenyl.
(13) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, R12 is phenyl, m is zero and X4 is xe2x80x94(CH2)3xe2x80x94.
(14) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula IX, R19 is benzhydryl and r is two.
(15) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula III, R8 is other than hydrogen and R9 is benzyhydryl.
(16) A compound to the formula Ic wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration.
(17) A compound of the formula lc wherein R3 is a group of the formula II wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, o is two, each of R6 and R7 is phenyl and ring AA is phenyl or indolinyl.
(18) A compound of the formula Ic wherein R3 is a group of the formula III wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, R1 is other than hydrogen, R9 is benzhydryl and ring AA is phenyl.
(19) A compound of the formula Ic wherein R3 is a group of the formula VII wherein R12 and the substituent at position xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, ring AA is phenyl, R12 is phenyl, each of R2, R13, R14, R15 and R16 is hydrogen, m is zero, X4 is xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94 and R1 is selected from S(O)vxe2x80x94(C1-C10)alkyl wherein v is zero, one or two, and 
and di-(C1-C6)alkylamino.
(20) A compound as defined in paragraph 19 above, wherein X4 is xe2x80x94(CH2)2xe2x80x94 and W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms.
(21) A compound as defined in paragraph 19 above, wherein X4 is xe2x80x94(CH2)3xe2x80x94 and W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms.
(22) A compound of the formula Ic, wherein R3 is a group of the formula IX wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, r is two and R19 is benzhydryl.
(23) A compound as defined in paragraph 22 above, wherein ring AA is phenyl, W1 is (C1-C5)alkoxy optionally substituted with from one to three fluorine atoms and R1 is selected from xe2x80x94S(O)vxe2x80x94(C1-C10)alkyl wherein v is zero, one or two, di-(C1-C6)alkylamino and 
(24) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from xe2x80x94S(O)vxe2x80x94(C1-C10)alkyl wherein v is zero, one or two, and 
(25) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1-C6)alkylamino or di-(C1-C6)alkylamino.
(26) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from xe2x80x94S(O)vxe2x80x94(C1xe2x80x94C10)alkyl wherein v is zero, one or two, and 
(27) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1-C6)alkylamino or di-(C1-C6)alkylamino.
(28) A compound as defined in paragraph 24 above, wherein W1 is attached at the xe2x80x9c2xe2x80x9d position of ring AA and R1 is attached at the xe2x80x9c5xe2x80x9d position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(29) A compound as defined in paragraph 25 above, wherein W1 is attached at the xe2x80x9c2xe2x80x9d position of ring AA and R1 is attached at the xe2x80x9c5xe2x80x9d position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(30) A compound as defined in paragraph 26 above, wherein W1 is attached at the xe2x80x9c2xe2x80x9d position of ring AA and R1 is attached at the xe2x80x9c5xe2x80x9d position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(31) A compound as defined in paragraph 27 above, wherein W1 is attached at the xe2x80x9c2xe2x80x9d position of ring AA and R1 is attached at the xe2x80x9c5xe2x80x9d position of ring AA, relative to the point of attachment of the NR2R3 containing side chain.
(32) A compound as defined in paragraph 13 above, wherein ring AA is phenyl, W1 is selected from isopropoxy, OCF3, OCH3, OCHF2, and OCH2CF3, and R1 is selected from xe2x80x94S(O)vxe2x80x94(C1-C10)alkyl wherein v is zero, one or two, and (C1-C10)alkyl-Nxe2x80x94SO2xe2x80x94(C1-C10)alkyl.
(33) A compound selected from the group consisting of:
(2S, 3S)-N-(2-methoxy-5-methylsulfonylphenyl)-methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(2-methoxy-5-methylthiophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(2-methoxy-5-dimethylaminophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S, 3S)-N-(5-trifluoroacetylamino-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo-[2.2.2]octan-3-amine.
(34) A compound of the formula Ic, wherein R3 is a group of the formula VII, m is zero, each of R13, R15, R16 and R17 is hydrogen, R12 is phenyl, R14 is 
ring AA is phenyl, W1 is (C1-C3)alkoxy and R1 is selected from (C1-C5)alkyl, xe2x80x94SCH3, SO2CH3, SOCH3, (C1-C6)alkylamino and di-(C1-C6)alkyl-amino.
(35) A compound of the formula Ic, having the formula 
(36) A compound of the formula Id wherein R61, R10, R11 and R13 are phenyl, R8 is hydrogen, R9 is phenyl optionally substituted with chlorine, fluorine, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms or (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, m is 0 and n is 3 or 4.
(37) A compound of the formula Id that is selected from the group consisting of:
(2S, 3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;
(2S, 3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S, 3S)-3 (-5-tert-butyl-2-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)-benzyl]amino-2-phenylpiperidine;
(2S, 3S)-3-(5-tert-butyl-2-trif luoromethoxybenzyl) amino-2-phenylpiperidine;
(2S, 3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
(2S, 3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S, 3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)-aminopiperidine; and
(2S, 3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine.
(38) A compound of the formula Id, wherein R3 is a group of the formula II wherein o is two or three and each of R6 and R7 is phenyl or substituted phenyl.
(39) A compound of the formula Id, wherein R3 is a group of the formula III, R8 is hydrogen and R9 is phenyl or substituted phenyl.
(40) A compound of the formula Id, wherein R3 is a group of the formula IV wherein 1 is one or two and each of R10 and R11 is phenyl or substituted phenyl.
(41) A compound of the formula Id, wherein R3 is a group of the formula V wherein n is zero or one and each of R10 and R11 is phenyl or substituted phenyl.
(42) A compound of the formula Id, wherein R3 is a group of the formula VI wherein p is one and each of R10 and R11 are phenyl or substituted phenyl.
(43) A compound of the formula Id, wherein R3 is a group of the formula VII wherein q is two, three or four, m is zero and R12 is phenyl or substituted phenyl.
(44) A compound of the formula Id, wherein R3 is a group of the formula VIII wherein y is zero, x is zero or one, z is three or four, m is zero and R12 is phenyl or substituted phenyl.
(45) A compound of the formula Id wherein R3 is a group of the formula VII, R6, R14, R13 R16 and R15 are hydrogen, R12 is phenyl, X1 is 2-methoxy, X2 and X3 are independently selected from hydrogen, chlorine, fluorine, methyl, (C1-C6)alkoxy and trifluoromethane, m is 0 and q is 3 or 4.
(46) A compound of the formula Id wherein R3 is a group of the formula VII and said compound is selected from the group consisting of:
cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;
cis-3-(2-trifluoromethylbenzylamino)-2-phenyl-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;
3-(2-methoxybenzylamino)-4-methyl-2-phenyl-piperidine;
3-(2-methoxybenzyla,ino)-5-methyl-2-phenyl-piperidine;
3-(2-methoxybenzylamino)-6-methyl-2-phenyl-piperidine;
(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S, 3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
(2S, 3S)-1-(6-hydroxy-hex-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
(2S, 3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxy-benzylamino)-2-phenylpiperidine;
(2S, 3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
(2S, 3S)-1-(5,6-dihydroxyhex-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenyl-piperidine;
(2S, 3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S, 3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxy-5-methylbenzylamino)-2-phenyl-piperidine;
(2S, 3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenyl-piperidine;
(2S, 3S)-3-(2-methoxybenzylamino)-1-(5-N-methyl-carboxamidopent-1-yl)-2-phenylpiperidine;
(2S, 3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S, 3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxy-benzylamino)-2-phenylpiperidine;
(2S, 3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
(2S, 3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S, 3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenyl-piperidine;
(2S, 3S)-3-(2,5-dimethoxybenzylamino)-2-phenyl-piperidine;
cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenyl-piperidine;
cis-3-(4, 5-difluoro-2-methoxybenzylamino)-2-phenyl-piperidine;
cis-3-(2, 5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;
ois-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;
cis-1-(5,6-dihydroxyhex-1-yl)-3-(2,5-dimethoxy-benzylamino)-2-phenylpiperidine;
cis-2-phenyl-3-[-2(prop-2-yloxy)benzylamino]piperidine;
cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxy-phenyl)piperidine hydrochloride;
cis-3-(5-chloro-2-methoxybenzyl) amino-2-(3-methoxy-phenyl)piperidine dihydrochloride;
cis-3-(5-chloro-2-methoxybenzyl) amino-2-(3-chloro-phenyl)piperidine dihydrochloride;
3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;
(2S, 3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine;
(2S, 3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine; and
(2S, 3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenyl-piperidine.
(47) A compound of the formula Id, wherein R3 is a group of the formula II or III and said compound is selected from the group consisting of:
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenyl-methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenyl-methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S, 3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.
(47A) a compound of the formula Ie that is selected from the group consisting of:
2,4-dimethylthiazole-5-sulfonic acid[4-methoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
N-(4,5-dimethylthiazol-2-yl)-N-[4-methoxy-3-((2S, 3S)-2-phenylpiperidin-3-yl-aminomethyl)phenyl]-methanesulfonamide;
{5-[(4,5-dimethylthiazol-2-yl)methylamino]-2-methoxybenzyl}-((2S, 3S)-2-phenylpiperidin-3-yl)amine;
{5-(4,5-dimethylthiazol-2-ylamino)-2-methoxybenzyl}-((2S, 3S)-2-phenylpiperidin-3-ylamine;
4,5-dimethylthiazole-2-sulfonic acid methyl-[3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)-4-trifluoromethoxyphenyl]-amide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-methylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isopropylamide;
2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide; and
2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3-((2S, 3S)-2-phenylpiperidin-3-ylaminomethyl)phenyl]-isobutylamide.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula 
wherein W is Y or X(CH2)n;
Y is optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl or optionally substituted (C3-C8)cycloalkyl;
X is optionally substituted (C1-C6)alkoxy, hydroxy, CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1, CONR1OR2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
Ar1, Ar2 and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl;
and R1, R2 and R3 are independently selected from hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C3-C8)cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C1-C5)heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1-C4)alkyl, (C1-C4)alkoxy, trifluoromethyl and trifluoromethoxy; and wherein the substituents on the foregoing substituted (C1-C5)heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C1-C4)alkyl when attached to a ring sulfur atom, and are independently selected from oxygen and (C1-C4)alkyl when attached to a ring nitrogen atom;
and wherein the substituents on said substituted Ar1 groups are independently selected from (C1-C6)alkyl optionally substituted with from one to three halo groups, (C1-C6)alkoxy optionally substituted with from one to three halo groups, (C1-C6)alkylsulfinyl, (C2-C6)alkenyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, and di-(C1-C6)alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C1-C6)alkylsulfonyl, or (C1-C6)alkylsulfinyl group;
and wherein the substituents on said substituted Ar2 and Ar3 groups are independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, di-(C1-C4)alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C1-C4)alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (54) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(48) A compound of the formula X, wherein W is X(CH2)n.
(49) A compound of the formula X, wherein W is Y.
(50) A compound of the formula X, wherein Ar1 is substituted aryl and W is Y.
(51) A compound of the formula X, wherein Art is mono-, di- or tri-substituted phenyl and W is Y.
(52) A compound of the formula X, wherein Ar1 is phenyl disubstituted at the 2- and 5-positions and W is Y.
(53) A compound of the formula X, wherein Ar1 is paramethoxyphenyl, each of Ar2 and Ar3 is phenyl and W is Y.
(54) A compound of the formula X that is selected from the group consisting of:
(3R, 4S, 5S, 6S)-N,N-diethyl-5-(5-isopropyl-2-methoxy-benzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxybenzylamino)-6-diphenyl-methyl-1-azabicyclo-[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxy-benzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylsulfinylbenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-trifluoromethoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylsulfonylbenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4s, 5S, 6S)-5-(5-N-methylmethanesulfonylamino-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylsulfinylbenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-trifluoromethoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;
(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylsulfonylbenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid; and
(3R, 4S, 5S, 6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.q;, during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula 
wherein R1 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (1-C6)alkoxy, amino, trihaloalkxy (e.g., trifluoromethoxy), 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7)cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, amino, phenyl, trihaloalkoxy (e.g., trifluoromethoxy), (C1-C6)alkylamino, 
one of R5 and R6 is hydrogen and the other is selected from hydroxymethyl, hydrogen, (C1-C3)alkyl, (C1-C8)acyloxy-(C1-C3)alkyl, (C1-C8)alkoxymethyl and benzyloxymethyl;
R7 and R8 are independently selected from hydrogen, (C1-C3)alkyl and phenyl;
R9 is selected from methyl, hydroxymethyl, 
xe2x80x83R16OCO2CH2xe2x80x94, (C1-C4)alkyl-CO2CH2xe2x80x94, xe2x80x94CONR17R18, R17R18NCO2xe2x80x94, R19OCO2xe2x80x94, C6H5CH2CO2CH2xe2x80x94, C6H5CO2CH2xe2x80x94, (C1-C4)alkyl-CH(OH)xe2x80x94, C6H5CH(OH)xe2x80x94, C6H5CH2CH(OH)xe2x80x94, CH2halo, R20SO2OCH2, xe2x80x94CO2R16 and R21 CO2xe2x80x94;
R10 and R11 are independently selected from hydrogen, (C1-C3)alkyl and phenyl;
R12 is hydrogen, benzyl or a group of the formula 
xe2x80x83wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R23;
R13, R14, R15 l , R16, R17, R18, R19, R20, R21 and R24 are independently selected from hydrogen, (C1-C3)alkyl and phenyl;
R22 and R23 are independently selected from hydrogen, ydroxy, halo, amino, carboxy, carboxy(C1-C6)alkyl, (C1-C6)alkylamino, di-(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)xe2x80x94
xe2x80x83(C1-C6) straight or branched alkyl, (C3-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6)alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, amino, (C1-C6)-alkylamino, 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached form a second pyrrolidine ring; with the proviso that when R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R12 is absent or R12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Compounds of the formula XI that contain two pyrrolidine rings may be represented by one of the following two structures, depending on whether R12 is present or absent. 
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (55) through (59) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(55) A compound of the formula XI wherein R1 is benzhydryl.
(56) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, xe2x80x94CO2R16, xe2x80x94CONR17R18, R14R15NCO2CH2xe2x80x94, R16OCO2CH2xe2x80x94, (C1-C4)alkyl-CO2CH2xe2x80x94, C6H5CH2CO2CH2xe2x80x94, xe2x80x94(CH2halo and R20SO2OCH2xe2x80x94, and R12 is hydrogen or benzyl.
(57) A compound of the formula XI wherein R1 is phenyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substiuents, each of R5, R6, R7, R8, R10, and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, xe2x80x94CO2R18, xe2x80x94CONR17R18, R14R15NCO2CH2CH2xe2x80x94, R16OCO2CH2xe2x80x94, (C1-C4)alkyl-CO2CH2xe2x80x94, xe2x80x94CH2halo, R20SO2OCHxe2x80x94, and R12 is hydrogen or benzyl.
(58) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, R11 and R13 is hydrogen, and wherein R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen).
(59) A compound of the formula XI that is selected from the group consisting of:
(2S, 3S, 4R)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carbomethoxymethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carboxymethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(2-dimethylamino-carbamoylethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-((2-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2S, 3S, 4R)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylaminoj-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-((2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-methoxyethyl)-pyrrolidine;
(2S, 3S, 4R)-2-diphenylmethyl-3-((2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-methoxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methyl-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)-methylamino]-bicyclo[2.2.1]-heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]bicyclo-[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-((2-methoxy-5-trifluoromethoxyphenyl)methylamino)bicyclo-[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]bicyclo-[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylpropyl)phenyl)methylamino]bicyclo-[2.2.1]heptane;
(1SR, 2SR, 3SR, 4RS)-1-aza-2-phenyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR, 2SR, 3RS, 4RS)-1-aza-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(2SR, 3SR, 4RS)-N-1-phenylmethyl-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)-pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methyl-1-propyl)phenyl)methylamino]-4-(2-hydroxy-ethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-trifluoro-methoxy-5-(i,l-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-chlorophenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxyphenyl)methyl-amino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxy-ethyl)pyrrolidine; and
(2SR, 3SR, 4RS)-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxy-ethyl)pyrrolidine.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (etg., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein R1 is hydrogen, (C1-C8)alkyl, a saturated (C6-C10) carbocyclic ring system containing two fused rings, a saturated (c6-C10)carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms and (C1-C8)alkoxy optionally substituted with from one to three fluorine atoms;
R2 is hydrogen, benzyl or a group of the formula 
xe2x80x83wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R9;
R8 and R9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1-C6)alkyl, ((C1-C6)alkylamino, di-(C1-C6)alkylamino, (C1-C6)alkoxy, 
xe2x80x83(C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6)alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, amino, (C1-C6)-alkylamino, 
xe2x80x83and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
R4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, phenyl, amino, (C1-C8)alkylamino, 
R3 is hydrogen, (C3-C8)cycloalkyl, (C1-C6) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, and (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
R5 is hydrogen, (C1-C6)alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms and (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
R6 is selected from hydrogen, (C1-C6) straight or branched alkyl, (C1-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy, trifluoromethyl, amino, trihaloalkoxy (e.g. ,trif luoromethoxy), 
xe2x80x83and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R12 is hydrogen, (C1-C3)alkyl or phenyl;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (60) through (62) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(60) A compound of the formula XII wherein R2 is hydrogen, or R2 and R1, together with the nitrogen to which they are attached, form a monocyclic ring containing five to seven carbon atoms; R3 is hydrogen, methyl or phenyl; R5 is hydrogen; R4 is phenyl or indanyl, wherein said phenyl or indanyl may optionally be substituted with from one to three substituents independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C1-C6)alkylamino, xe2x80x94C(O)NHxe2x80x94(C1-C8)alkyl, (C1-C6)alkyl-C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94C(O)H, xe2x80x94CH2OR12, xe2x80x94NH(C1-C6)alkyl, xe2x80x94NHC(O)H, xe2x80x94NHC(O)xe2x80x94(C1-C6)alkyl, xe2x80x94NHSO2(C1-C6)alkyl and (C1-C6)alkyl-Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl; and R6 is phenyl.
(61) A compound of the formula XII wherein R1 is alkyl, R6 is unsubstituted phenyl, R4 is a monosubstituted or disubstituted aryl group that is substituted at the C-2 position with an alkoxy group or substituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxy group, or substituted in such manner at both C-2 and C-5 positions (i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy or trihaloalkoxy group at the C-5 position), and each of R2, R3 and R5 is hydrogen.
(62) A compound of the formula XII that is selected from the group consisting of:
1-N-cyclohexyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-Nxe2x80x2-[(2-methoxy-5-trifluoromethoxyphenyl)methyl]-1,2-ethanediamine;
1-N-pyrrolidyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-methyl-1-phenyl-2-Nxe2x80x2-[(2-nethoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopentyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl) methyl]-1,2-ethanediamine;
1-N-propyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-phenylmethyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl) methyl]-1,2-ethanediamine;
1-N-cyclooctyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclobutyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(2-adamantyl)-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl) methyl]-1,2-ethanediamine;
1-N-(1,1-dimethylethyl)-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopropyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl) methyl]-1,2-ethanediamine;
1-N-isopropyl-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(1-phenylethyl)-1-phenyl-2-Nxe2x80x2-[(2-methoxy-phenyl)methyl]-1,2-ethanediamine;
1-N-(2-norbornyl)-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-Nxe2x80x2-[(2-methoxy-5-tert-butylphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-Nxe2x80x2-[(2-methoxy-5-isopropylphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-Nxe2x80x2-[(2-methoxy-4,5-dimethylphenyl)methyl]-1,2-ethanediamine; and
1-N-cyclohexyl-1-N-(6-hydroxyhexyl)-1-phenyl-2-Nxe2x80x2-[(2-methoxyphenyl)methyl]-1,2-ethanediamine.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
xe2x80x83wherein R1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
R2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
R3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (63) through (65) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(63) A compound of the formula XIII, wherein R1 is phenyl or substituted phenyl.
(64) A compound of the formula XIII, wherein R1 is methoxyphenyl.
(65) A compound of the formula XIII, wherein said compound is (xc2x1)-cis-9-diphenylmethyl-N-((2-methoxy-phenyl)methyl)-10-azatricyclo[4.4.1.05.7]undecan-8-amine.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (eg, in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8;
w is an integer from 0 to 2;
y is an integer from 1 to 4;
z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH2)z may optionally be substituted with R4;
R1 is hydrogen or (C1-Ca)alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R2 is a group selected from hydrogen, (C1-C6)straight or branched alkyl, (C3-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2-C6)alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl(C2-C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, amino, (C1-C6)-alkylamino, 
R5 is hydrogen, phenyl or (C1-C6)alkyl;
or R2 and R5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
R3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3-C7)cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, phenyl, amino, (C1-C6)alkylamino, (C1-C6)dialkyl amino, 
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (xe2x95x90O), nitrile, (C1-C6)alkylamino, di-(C1-C6)alkylamino, (C1-C6)alkoxy, 
xe2x80x83and the groups set forth in the definition of R2; 
xe2x80x83NHCH2R9, NHSO2R9 or one of the groups set forth in any of the definitions of R2, and R4;
R8 is oximino (xe2x95x90NOH) or one of the groups set forth in any of the definitions of R2, and R4;
R9 is (C1-C6)alkyl, hydrogen, phenyl or phenyl (C1-C6)alkyl;
with the proviso that (a) when m is 0, R8 is absent and R6 is hydrogen, (b) neither R4, R6, nor R8 can form, together with the carbon to which it is attached, a ring with R5, (c) the sum of y and z must be less than 7; or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (66) through (68) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(66) A compound of the formula XIV, wherein R2 is a radical selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6) alkyl, (C1-C6)alkoxy, trifluoromethyl, amino, (C1-C6)-alkylamino, 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
(67) A compound of the formula XIV, wherein R2 is a group selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trif luoromethyl, amino, (C1-C6)-alkylamino, 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (=o), nitrile, (C1-C6)alkylamino, di-(C1-C6)alkylamino, (C1-C6)alkoxy, 
xe2x80x83(C1-C6)alkyl and phenyl.
(68) A compound of the formula XIV, wherein said compound is (3RS, 4RS)-3-phenyl-4-(2-methoxybenzyl) amino-2-azabicyclo[3.3.1]nonane.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (eg, during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal a compound of the formula 
wherein X1 is C1-C5 alkoxy or halosubstituted (C1-C5)alkoxy;
X2 is hydrogen, halogen, (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylsulfinyl, (C1-C5)alkylsulfonyl, halosubstituted (C1-C5)alkyl, halosubstituted (C1-C5)alkoxy, (C1-C5)alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C1-C5)alkylsulfonylamino (which may be substituted by halogen), 
xe2x80x83(which may be substituted by halogen in the alkylsulfonyl moiety), (C1-C5)alkanoylamino (which may be substituted by halogen) or 
xe2x80x83(which may be substituted by halogen in the alkanoyl moiety);
Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
A is Yxe2x80x94(CH2)mxe2x80x94CH(R2)xe2x80x94(CH2)nxe2x80x94NR1xe2x80x94;
R1 is hydrogen, (C1-C5)alkyl, benzyl or xe2x80x94(CH2)pxe2x80x94Y;
R2 is hydrogen, (C1-C5)alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or xe2x80x94(CH2)pxe2x80x94Y;
Y is xe2x80x94CN, xe2x80x94CH2Z or xe2x80x94COZ;
Z is hydroxy, amino, (C1-C5)alkoxy, (C1-C5)alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;
m, n and p are each, independently, 0, 1, 2 or 3; and
R1 and R2 may be connected to form a ring;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (ecg, during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(69) A compound of the formula XV, wherein said compound is selected from the group consisting of:
(3R, 4S, 5S, 6S)-N-carbamoylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-N-carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-3-(2-carbamoylpyrrolidin-1-yl) carbonyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane;
(3R*, 4S*, 5S*, 6S*)-N-(1-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-N-(1-carbamoyl-3-methylbutyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide; and
(3R, 4S, 5S, 6S)-N-(2-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein R1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms, trif luoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)-alkylamino, di-(C1-C6)alkylamino, 
(C1-C4)alkoxy(C1-C4)alkyl, xe2x80x94S(O)vxe2x80x94(C1-C10)-alkyl wherein v is zero, one or two, xe2x80x94S(O)v-aryl wherein v is zero, one or two, xe2x80x94O-aryl, xe2x80x94SO2NR4R5 wherein each of R4 and R5 is, independently, (C1-C6)alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, 
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, xe2x80x94N(SO2xe2x80x94(C1-C10)alkyl)2 and 
and wherein the aryl moieties of said xe2x80x94S(O)v-aryl, xe2x80x94O-aryl and 
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)alkoxy and halo;
or R1 is phenyl substituted with a group having the formula 
xe2x80x83wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R1;
R2 is selected from (C1-C6) straight or branched alkyl, (C3-C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C1-C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6)alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents, independently selected from halo, nitro, (C1-C10)alkyl optionally substituted with from one to three fluorine atoms, (C1-C10)alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)-alkylamino, 
xe2x80x83and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R4;
R3 is selected from 
xe2x80x83NHCH2R8, SO2R1, AR9, CO2H and the radicals set forth in the definitions of R2, R6 and R7;
A is CH2, nitrogen, oxygen, sulfur or carbonyl;
R8 is (C1-C6)alkyl, hydrogen, phenyl or phenyl (C1-C6)alkyl;
R4 is selected from oximino (xe2x95x90NOH) and the radicals set forth in the definitions of R2, R6 and R7;
R9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae 
xe2x80x83wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH2)n and (CH2)n+1 may be optionally substituted with (C1-C6)alkyl or (C2C6)spiroalkyl; and either any one pair of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3-C5) fused carbocyclic ring;
X is (CH2)q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R6, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R7;
R6 and R7 are independently selected from hydrogen, hydroxy, halo, amino, oxo (xe2x95x90O), cyano, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)alkylamino, di-(C1-C6)alkylanino, 
xe2x80x83and the radicals set forth in the definition of R2; and
Y is (CH2)z wherein z is zero or one;
with the proviso that: (a) when A is xe2x80x94(CH2)xe2x80x94 or carbonyl, R9 cannot be furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl or thienyl; (b) when m is zero, one of R3 and R4 is absent and the other is hydrogen; and (c) when R6 or R7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R6 or R7, respectively, must be a substituent wherein the point of attachment is a carbon atom;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (70)-(75) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(70) A compound of the formula XVI wherein z is one.
(71) A compound of the formula XVI wherein q is three.
(72) A compound of the formula XVI wherein q is three, m is zero, R3 is hydrogen and R4 is absent.
(73) A compound of the formula XVI wherein R1 is phenyl substituted with from one to three substituents independently selected from (C1-C6)alkyl optionally substituted with from one to three fluorine atoms and (C1-C6)alkoxy optionally substituted with from one to three flourine atoms.
(74) A compound of the formula XVI wherein z is one, m s zero, R4 is absent, and each of R3, R6 and R7 is hydrogen.
(75) A compound of the formula XVI that is selected from the group consisting of:
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-phenyl-7-phenyl-1,8-diazaspiro[5.5]undecane; and
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane.
Other compounds of the formula I include the following:
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(5-chloro-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1, 6xcex1 (R*)]]-3-(5-isopropyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(5-tertbutyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-methoxy-5-(N-methyl-N-methylsulfonylaminophenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-iodophenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-methoxy-4-methylphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-isopropoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,6xcex1 (R*)]]-3-(2-difluoromethoxy-5-trifluoromnethoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(xc2x1)-[3R-[3xcex1,5xcex1 (R*)]]-3-(2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(xc2x1)-[3R-[3xcex1,5xcex1 (R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(xc2x1)-[3R-[3xcex1,5xcex1 (R*)]]-3-(5-chloro-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(xc2x1)-[3R-[3xcex1,5xcex1 (R*)]]-3-(5-isopropyl-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane; and
(xc2x1)-[3R-[3xcex1,5xcex1 (R*)]]-3-(5-tert.butyl-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein Ar1 and Ar2 are each independently aryl or substituted aryl;
R1 is alkyl having from 1 to 6 carbon atoms;
R2 is hydrogen or alkyl having from 1 to 6 carbon atoms;
and either X and Y are taken separately and they are each, independently, hydrogen, dialkylphosphoryl having from 2 to 12 carbon atoms, alkyl having from 1 to 6 carbon atoms; or X and Y are taken together and they represent a hydrocarbon chain having 3, 4, or 5 carbon atoms, optionally containing up to 2 double bonds and optionally having 1 or 2 substituents selected from oxo, hydroxy and alkyl having from 1 to 6 carbon atoms;
provided that when X and Y are taken together they are attached to adjacent carbon atoms; and
provided that if either X or Y is hydrogen, then the other one must be alkenyl or alkynyl;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
The term xe2x80x9calkylthioxe2x80x9d is used in formula XVII to mean xe2x80x94SR4 (R4 is alkyl) including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio and the like.
The term xe2x80x9cdialkylphosphorylxe2x80x9d is used in formula XVII to mean xe2x80x94P(O) (OR5) (OR6) (R5 and R6 are alkyl) including, but not limited to, diethylphosphoryl, ethylmethylphosphoryl and the like.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e, in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (76)-(79) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(76) Compounds of formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen, X is alkenyl or alkynyl and Y is hydrogen.
(77) Compounds of the formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen and X and Y are each alkyl.
(78) Compounds of the formula XVII wherein Ar1 and Ar2 are each phenyl, R1 is methyl, R2 is hydrogen and X and Y represent CH2CH2CH2 or CH2CH2CH2CH2.
(79) A compound of the formula XVII that is selected from:
(2S, 3S)-N-(5-Isopropenyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(2-Methoxy-5-vinylphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(2-Methoxy-4,5-dimethylphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5,6,7,8-Tetrahydro-3-methoxy-2-naphthyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(5-Methoxyindan-6-yl)methyl-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-3-(2,4-Dimethoxy-5-ethylbenzylamino)-2-diphenylmethyl-1-azabicyclo[2.2.2]octane; and
(2S, 3S)-2-Diphenylmethyl-N-[2-methoxy-5-(diethylphosphoryl)phenyl]methyl-1-azabicyclo[2.2.2]octan-3-amine.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.c., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 
wherein Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
X is xe2x80x94CONR3R4, xe2x80x94CO,R3, xe2x80x94CH2OR3, xe2x80x94CH2NR3R4 or xe2x80x94CONR3OR4;
R1, R3 and R4 are each, independently, hydrogen or alkyl having 1 to 4 carbon atoms;
R2 is alkyl having 1 to 4 carbon atoms;
Y is alkylsulfonyl having 1 to 4 carbon atoms, N-alkyl-N-alkanoylamino (which may be substituted by halogen in the alkanoyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkanoyl moieties, N-alkyl-N-alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety) having 1 to 4 carbon atoms in the alkyl and the alkyl sulfonyl moieties, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, halosubstituted alkyl having 1 to 4 carbon atoms, alkylamino having 1 to 4 carbon atoms, alkanoylamino (which may be substituted by halogen) having 1 to 4 carbon atoms or alkylsulfonylamino (which may be substituted by halogen) having 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (80)-(86) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(80) A compound of the formula XVIII wherein Ar1 and Ar2 are each phenyl.
(81) A compound as described in paragraph (80) wherein R2 is methyl and R1 is hydrogen.
(82) A compound as described in paragraph (81) wherein X is at the 3-position of the quinuclidine ring and X is carboxy or aminocarbonyl.
(83) A compound as described in paragraph (82) wherein Y is said alkenyl.
(84) A compound as described in paragraph (83) wherein Y is isopropenyl.
(85) A compound as described in paragraph (82) wherein Y is methylsulfonyl, N-acetyl-N-methylamino or N-methyl-N-methylsulfonylamino.
(86) A compound of the formula XVIII that is selected from:
(3R, 4S, 5S, 6S)-5-(5-Isopropenyl-2-methoxybenzyl-amino)-25 6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-6-Diphenylmethyl-5-(2-methoxy-5-methylsulfonylbenzylamino)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-5-5-[N-Acetyl-N-methylamino)-2-methoxy benzyl amino]-6-diphenyl methyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R, 4S, 5S, 6S)-6-Diphenylmethyl-5-[2-methoxy-5-(N-methyl-N-methylsulfonylamino)benzylamino]-1-azabicyclo[2.2.2]octane-3-carboxamide; and
(3R, 4S, 5S, 6S)-6-Diphenylmethyl-5-(2-methoxy-5-methylsulfonylbenzylamino)-1-azabicyclo[2.2.2]octane-3-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (exg., during open heart surgery), excitotoxic neuronal damage (eag., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal a compound of the formula 
wherein R is C1-C6 alkyl;
X is C1-C6 alkyl having one or more substituents bonded through a heteroatom;
Ar1 and Ar2 are each, independently, aryl optionally substituted by one C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono C1-C6 alkylamino, di C1-C6 alkylamino, halosubstituted C1-C6 alkyl, or halosubstituted C1-C6 alkoxy;
Y is hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl, Zxe2x80x94(CH2)pxe2x80x94, or Wxe2x80x94(CH2)mxe2x80x94CHR2xe2x80x94(CH2)nxe2x80x94NR1CO wherein Y is at the 4-, 5- or 6-position on the quinuclidine ring;
R1 is hydrogen, C1-C6 alkyl, benzyl or xe2x80x94(CH2)rxe2x80x94W;
R2 is hydrogen or C1-C6 alkyl which may be substituted by one hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or xe2x80x94(CH2)rxe2x80x94W;
Z is C1-C6 alkoxy, xe2x80x94CONR4R5, xe2x80x94CO2R4, xe2x80x94CHR4OR5, xe2x80x94CHR4NR5R6, xe2x80x94COR4, xe2x80x94CONR4OR5 or optionally substituted aryl;
each W is independently cyano, hydroxymethyl, C2-C6 alkoxymethyl, aminomethyl, mono C1-C6 alkylaminomethyl, di C1-C6 alkylaminomethyl, carboxyl, carbamoyl or C1-C6 alkoxycarbonyl;
R4, R5 and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or an optionally substituted aryl or heterocyclic group;
p is 0 to 6; and
m, n and r are each, independently, 0 to 3;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (87)-(91) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(87) A compound of the formula XIX wherein X is C1-C6 alkyl having one or two substituents selected from hydroxy, halogen, C1-C6 alkoxy, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C1-C6 alkylthio, mono C1-C6 alkylamino, di C1-C6 alkylamino, amino, cyano and azido.
(88) A compound of the formula XIX as described in paragraph (87) wherein R is methyl and the OR group is at the 2-position; Ar1 and Ar2 are each phenyl, monochlorophenyl or monofluorophenyl; Y is hydrogen or Zxe2x80x94(CH2)pxe2x80x94, wherein Z is C1-C6 alkoxy, xe2x80x94CONR4R5, xe2x80x94CO2R4, xe2x80x94CHR4OR5, xe2x80x94CHR4NR5R6, xe2x80x94COR4 or xe2x80x94CONR4OR5; and Y is at the 5- or 6-position.
(89) A compound as described in paragraph (88) wherein X is C1-C6 alkyl having one or two substituents selected from hydroxy, C1-C6 alkoxy and C1-C6 alkylthio; Ar1 and Ar2 are each phenyl; and Y is hydrogen or carboxy.
(90) A compound is described in paragraph (89) wherein x is xe2x80x94C(CH3)2OH, xe2x80x94C(OH) (CH3) CH2OH, xe2x80x94C(CH3)2OCH3 or xe2x80x94C(CH3)2SCH2CH3.
(91) A compound as described in paragraph (90) that is selected from:
(2S, 3S)-N-[5-(1-hydroxy-1-methylethyl)-2-methoxy-phenyl]methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S, 3S)-N-(2-methoxy-5-[1-methoxy-1-methylethyl)phenyl]methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(3R, 4S, 5S, 6S)-3-[5-(1-hydroxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid;
(2S, 3S)-2-diphenylmethyl-N-[5-(1-hydroxy-1-hydroxymethylethyl)-2-methoxyphenyl]methyl-1-azabicyclo[2.2.2]octan-3-amine;
(3R, 4S, 5S, 6S)-3-[5-(1-methoxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid;
(3R, 4S, 5S, 6S)-3-[5-(1-hydroxy-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid; and
(3R, 4S, 5S, 6S)-3-[5-(1-ethylthio-1-methylethyl)-2-methoxyphenyl]methylamino-6-diphenylmethyl-1-azabicyclo[2.2.2]octan-5-carboxylic acid.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal a compound of the formula 
wherein X and Y are each hydrogen, halo, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl or tri C1-C6 alkylsilyl;
Ar1 and Ar2 are each aryl optionally substituted by halo;
A is xe2x80x94COxe2x80x94 or xe2x80x94(CH2)xe2x80x94;
Zxe2x80x94Axe2x80x94 is at the 2 or 3 position on the quinuclidine ring;
Z is hydroxy, C1-C6 alkoxy, NR1R2 or W1xe2x80x94(CH2)mxe2x80x94CHR4xe2x80x94(CH2)nxe2x80x94NR3 wherein
R1 and R2, when taken separately, are each hydrogen or C1-C6 alkyl;
R1 and R2, when taken together with the nitrogen atom to which they are attached, represent piperidino, pyrrolidino, morpholino, thiomorpholino or piperazino;
R3 is hydrogen, C1-C6 alkyl, benzyl or xe2x80x94(CH2)rxe2x80x94W2;
R4 is hydrogen or C1-C6 alkyl which may be substituted by hydroxy, amino, methylthio, mercapto, benzyl, 4-hydroxylbenzyl, 3-indolylmethyl or xe2x80x94(CH2)sxe2x80x94W3;
R3 and R4, when taken together, represent CH2 or CH2CH2;
W1, W2 and W3 are each cyano, hydroxymethyl, C1-C6 alkoxymethyl, aminomethyl, (C1-C6 alkylamino)methyl, (di C1-C6 alkylamino)methyl, carboxyl, (C1-C6 alkyl)carbamoyl, or (di C1-C6 alkyl)carbamoyl, carbamoyl or (C1-C6 alkoxy)carbonyl; and
m, n, r and s are each 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such disorder.
As used in formula XX, the term xe2x80x9calkylthiolxe2x80x9d means xe2x80x94S-alkyl, including but not limited to methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like;
As used in formula XX, the term xe2x80x9calkylsulfonylxe2x80x9d means xe2x80x94SO2-alkyl including but not limited to methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like; and
As used in formula XX, the term xe2x80x9carylxe2x80x9d means aromatic radicals including but not limited to phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl and the like. These aryl groups can be substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, phenoxy, mono- or di-C1-C6 alkylamino and the like.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (92) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(92) A compound of the formula XX that is selected from the group consisting of:
(3S, 4R, 5S, 6S)-N-carbamoylmethyl-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-azabicyclo[2.2.2]octane-3-carboxamide;
(3S, 4R, 5S, 6S)-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-azabicyclo[2.2.2]octane-3-carboxamide;
(3S, 4RS, 5S, 6S)-N,N-(3-oxa-1,5-pentylene)-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S, 4 R, 5S, 6S )-6-diphenyl methyl-5-(3,5-dimethylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3S, 4R, 5S, 6S)-N,N-diethyl-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3S, 4R, 5S, 6S)-6-diphenylmethyl-5-(3-fluoro-5-trifluoromethylbenzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3S, 4R, 5S, 6S )-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-azabicyclo[2.2.2]octane-3-carboxylic acid; and
(3S, 4R, 5S, 6S)-N,N-dimethyl-6-diphenylmethyl-5-(3,5-bis(trifluoromethyl)benzyloxy)-1-azabicyclo[2.2.2]octane-3-carboxamide.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.c., during open heart surgery), excitotoxic neuronal damage (e.q, in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal a compound of the formula 
wherein Y is C2-C4 alkylene;
Z is a valence bond or C1-C6 alkylene;
R1 is phenyl, biphenyl, indanyl, naphthyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, quinolyl, phenyl C1-C6 alkyl- or benzhydryl, wherein each of the ring mnoieties may optionally be substituted by one or more substituents independently selected from halogen, C1-C6 alkyl, halosubstituted C1-C6 alkyl, C1-C6 alkoxy and halosubstituted C1-C6 alkoxy;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen, hydroxy, cyano, amino or carboxy; and
R4 represents a group of the formula (II) or (III) 
xe2x80x83wherein X1, X2 and X3 are each halo, hydrogen, nitro, C1-C6 alkyl, halosubstituted C1-C6 alkoxy, halosubstituted C1-C6 alkoxy, hydroxy, amino, C1-C6 alkylthio, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl;
Q1 and Q2 are each H2, oxygen or sulfur;
A is valence bond, methylene, oxygen, sulfur or NH;
R5 and R6 are each hydrogen or C1-C6 alkyl; and
R6 is hydrogen, halogen, C1-Cd alkyl, halosubstituted C1-C6 alkyl or C1-C6 alkoxy;
provided that when Z is a valence bond, R3 must be hydrogen;
or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
Preferred embodiments of this invention include methods of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (93) below, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder.
(93) A compound of the formula XXI that is selected from:
(2S*, 3S*, 4S*, 5R*)-4-carboxy-3-[N-(5-isopropyl-2-methoxybenzyl)amino]-5-methyl-2-phenylpyrrolidine and
(2S*, 3S*, 5S*)-5-carboxy-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-2-phenylpiperidine.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and 2-butenyl.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, refers to xe2x80x94O-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
The term xe2x80x9calkylthioxe2x80x9d, as used herein, unless otherwise indicated, refers to xe2x80x94S-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and t-butylthio.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, unless otherwise indicated, refers to cyclic hydrocarbon radicals including, but not limited to cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9cone or more substituents,xe2x80x9d as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
Compounds of the formulae I, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI contain chiral centers and therefore exist in different enantiomeric forms. The above definitions of these compounds include all optical isomers and all stereoisomers of such compounds, and mixtures thereof.